In certain instances, human pharmacogenetic disorders cause individuals to react very differently to the same dose of the same drug. The teratogenic, carcinogenic, or toxic effects of certain drugs and other foreign compounds (xenobiotics) also may reflect important genetically mediated differences among individuals. Accordingly, our laboratory has developed experimental model systems for studying drug metabolism with recombinant DNA technology, in cell culture, and among inbred strains of mice. We have found that the induction of more than two dozen drug-metabolizing enzyme activities is regulated by a genetic system called the (Ah) complex. Among the structural gene products are multiple forms of P-450 induced by way of the Ah receptor. Cloned cDNA associated with four distinctly different forms of P-450 has been isolated and characterized. These mouse genes cross-hybridize to the corresponding genes from rat, rabbit, and human. With such clones we hope to understand the mechanisms of P-450 induction by drugs, to gain insight into the evolution of P-450 (present in plasmids and all eukaryotes), and to develop sensitive tests to determine clinically who is at increased risk for various drug-induced birth defects, other forms of drug toxicity, and environmentally-caused malignancies.